This invention relates to edible, hardenable, prompt release coating compositions comprising microcrystalline cellulose (MCC), carrageenan (CGN) and at least one of a strengthening polymer or a plasticizer. The coatings of the present invention can be applied to pharmaceutical, including nutriceutical, and veterinary solid dosage forms, confectionery, seeds, animal feed, fertilizers, pesticide tablets and granules, and foods, are readily dispersed in aqueous media, and, when applied as a coating and ingested by, for example, a human, do not significantly retard or extend release of active ingredient(s) from a substrate coated therewith.
It is a common practice to coat pharmaceutical and veterinary tablets to obtain several advantages. Among these are to mask unpleasant tasting active ingredients with a barrier coat, to improve the surface characteristics of tablets to make them easier to swallow, to reduce the absorption of water or moisture which can potentially degrade the active ingredient or promote some other undesirable change in the tablet structure, and simply to make a more elegant appearing tablet.
Another very important function of a pharmaceutical or veterinary tablet coating is to improve the integrity of the tablet itself. Uncoated tablets are often subject to being abraded or chipped, causing a loss of active ingredient in the process. More dramatically, they may break into two or more pieces. One measure of a useful coating is its ability to prevent any of these physical degradations of tablet structure. The effectiveness of a coating material to prevent abrading, chipping, or breakage of the tablet is determined by friability testing.
Confectionery and foods may be coated with a formulation to preserve the confection or food from deteriorating by contact with the oxygen and the moisture in the atmosphere. Coatings also can provide improved appearance and desirable organoleptic properties to the food as well as preventing loss of flavor.
Seeds may be coated to preserve the viability of the seeds by protecting against moisture. They may also be coated as a means for increasing particle size to facilitate mechanical planting. A dye can be included in the coating formulation to identify the seeds as to quality, type, or some other designation. Frequently, a pesticide, e.g., a fungicide, is incorporated into the coating formulation to protect both the seed itself and the seedling that results from germination of the seed. In all cases, this coating must not decrease the viability of the seeds or interfere with germination when the seeds are planted in the soil.
Animal feed may be coated to improve its flowability, appearance and its resistance to powdering or dusting. In such applications, the coating may be formulated to include vitamins, hormones, antibiotics, or the like, to benefit the livestock which will consume the feed.
Fertilizers, in either granular or tableted forms, may be coated to retain the integrity of the form and, especially, to protect the fertilizer from moisture which can cause agglomeration during storage, which could make rapid, even application to the soil difficult or inconvenient.
Coating of tableted pesticide formulations serves to maintain the integrity of the tablets or granules until they are placed in water where they rapidly disintegrate, forming a solution or slurry to be applied to the soil or plants. A second, and equally important, function of the coatings on tablets containing pesticides is to prevent human contact with the pesticide, thereby increasing safety for those handling and applying the pesticide.
Currently, most commercially available edible coatings utilize a synthetic cellulosic polymer such as hydroxypropylmethylcellulose (HPMC). Other synthetic film-formers which are commonly used include ethylcellulose, methylcellulose, polyvinylpyrrolidone, and polydextrose. These coating materials may be used alone or in combination with secondary film-formers such as sodium alginate or propylene glycol alginate. The foregoing are usually used in combination with other ingredients including fillers, for example, lactose or maltodextrin; plasticizers, such as polyethylene glycols, dibutyl sebacate, and triethyl citrate; surfactants; and often coloring materials such as a food dye or pigment, including opacifiers such as titanium dioxide and the like.
In the preparation of a coating formulation to be sprayed, the film former is usually dissolved or dispersed in a solvent, for example, water, along with the other ingredients of the formulation. In aqueous systems, since many polymers require significant time to become fully hydrated, the coating formulation must frequently be prepared in advance of the time it is to be applied to the tablets. A common procedure is to prepare these coating formulations the day preceding the coating operation in order to assure adequate hydration of the polymers used in them.
A particular disadvantage of coatings based primarily on HPMC is that the coating may harden over time and therefore increase tablet disintegration times. An increase in disintegration time delays the bioavailability of the active ingredient at least in proportion to the increase in disintegration time. Many other agents commonly used in coating compositions are also known to delay release of pharmaceutical agents, such as enteric coatings which use polymeric film forming materials which are insoluble in water, or gastric fluid, some of these being specifically selected to by-pass both the stomach and small intestine and provide colonic release.
The coatings of this invention meet U.S. Pharmacopoeia standards for rapid or immediate dissolution (U.S.P. monograph 23) of active ingredients from tablets or other solid dosage forms coated with them. They provide prompt release or dissolution consistent with the release rates which is normally obtained with the uncoated tablets or other substrates. Thus, they do not adversely impact or retard release of active ingredients from a substrate coated with them. Further, the coatings of this invention are readily dispersed and rapidly hydrated in aqueous media for application to a coating substrate, and provide elegant coatings which have all the benefits of coatings now in commercial use without the drawbacks that are common to them.
It has been found that these and other advantages may be achieved in accordance with the present invention by a coating composition which comprises a unique combination of materials specifically adapted for a prompt release when placed aqueous media or ingested, e.g., by a human. The coating composition of the present invention comprises microcrystalline cellulose, carrageenan, and at least one of a strengthening polymer and a plasticizer. More specifically, the present invention provides a prompt release, edible, hardenable coating composition comprising 3% to 40% microcrystalline cellulose, 9% to 25% iota carrageenan, and at least one of a strengthening polymer, a plasticizer, or a surface active agent, as well as to dry coatings and aqueous dispersions thereof.
The present invention also provides pharmaceutical, including neutriceutical, and veterinary solid dosage forms, confectionery, seeds, animal feed, fertilizers, pesticide tablets and granules, and foods coated with the prompt release edible, hardenable composition of this invention.
For purposes of this application, the term xe2x80x9cediblexe2x80x9d is intended to mean food grade materials which are approved by regulatory authorities for use in pharmaceutical or food applications. The term xe2x80x9chardenablexe2x80x9d used to describe the coating compositions of this invention is intended to include only those coating compositions that are capable of being dried from an aqueous solution or dispersion thereof into a solid coating which resists abrasive forces, i.e. a hardened coating, as distinguished from those xe2x80x9cenrobingxe2x80x9d coatings on confections which set up into a soft coating that can be handled and packaged but which do not resist abrasive forces significantly. The terms xe2x80x9cimmediatexe2x80x9d, xe2x80x9crapidxe2x80x9d or xe2x80x9cpromptxe2x80x9d release as applied to dissolution rates or times for the coating compositions of this invention or tablets coated with the compositions of this invention means that the coatings of this invention meet U.S. Pharmacopoeia standards (U.S.P. monograph 23) for rapid or immediate dissolution of active ingredients from tablets or other solid dosage forms coated therewith. Thus, they provide prompt release or dissolution consistent with the release rates which is normally obtained with the uncoated tablets or other substrate. They do not, consistent with the pharmacopeia standards above, when placed in aqueous media or ingested by, e.g., a human, significantly impact or retard release or dissolution of tablets or other solid dosage forms coated therewith. For example, coatings made in accordance with the present invention are substantially or completely disintegrated and/or dissolved within less than 10 minutes after being ingested or placed in aqueous media. Thus, when a pharmaceutical solid dosage form is coated with the coating of this invention and ingested by a human or other animal, the coating of this invention is dissolved or disintegrated prior to leaving the stomach. In the specification, examples and claims which follow, all percentages are by dry weight of the composition. These definitions are intended to apply throughout this application unless a contrary meaning is clearly indicated.
The microcrystalline cellulose, either coprocessed with carrageenan or simply blended therewith, interacts with the carrageenan to provide important film-forming characteristics required to provide an elegant coating which is particularly useful in, for example, coating pharmaceutical and veterinary tablets, caplets, granules, and spheres which contain active ingredients which require release promptly after being placed in aqueous media or ingested.
Microcrystalline cellulose is a purified, partially depolymerized cellulose that is generally produced by treating a source of cellulose, preferably alpha cellulose in the form of a pulp from fibrous plants, with a mineral acid, preferably hydrochloric acid. The acid selectively attacks the less ordered regions of the cellulose polymer chain, thereby exposing and freeing the crystallite sites, forming the crystallite aggregates which constitute microcrystalline cellulose. These are then separated from the reaction mixture and washed to remove degraded by-products. The resulting wet mass, generally containing 40 to 60 percent moisture, is referred to in the art by several names, including hydrolyzed cellulose, microcrystalline cellulose, microcrystalline cellulose wetcake, or simply wetcake. This microcrystalline cellulose wetcake may be used as such or may be further modified, for example, by attrition and/or drying, and utilized in accordance with the present invention.
Microcrystalline cellulose may also be produced for use in the present invention using a steam explosion treatment. In this process, wood chips or other cellulosic materials are placed in a chamber into which super-heated steam is introduced. After being maintained for a period of about 1-5 minutes, the exit valve is opened rapidly, releasing the contents explosively and yielding microcrystalline cellulose. No additional acid need be introduced into the reaction mixture, since it is believed that the acidic materials in the wood chips and the elevated temperature and pressure hydrolyze the cellulose and degrade it. In addition to the specific forms of microcrystalline cellulose, the present invention also contemplates the use of other cellulose derivatives, including microreticulated cellulose, also known as microreticulated microcrystalline cellulose, and powdered cellulose such as a commercial material sold as xe2x80x9cSolka Floc(copyright).xe2x80x9dAs discussed in greater detail below, the microcrystalline cellulose preferred for use in the present invention is microcrystalline cellulose which has an average particle size below about 100 microns, preferably microcrystalline cellulose which been attrited or has an average particle size in the range of 1 to 50 microns, preferably 1 to 30 microns.
Carrageenan is used in combination with microcrystalline cellulose to form the elegant prompt release coatings of the present invention. Carrageenan for use in the present invention is a naturally derived carrageenan, including the grades further defined below as iota, kappa, and lambda carrageenan. The preferred type of carrageenan, a polysaccharide which is comprised of repeating galactose units and 3,6-anhydrogalactose units, that is suitable for the compositions of this invention is referred to as iota carrageenan. A rich source of iota carrageenan is the seaweed Eucheuma spinosum. The approximate content of anhydrogalactose units in iota carrageenan is 30% whereas kappa carrageenan has 34% anhydrogalactose units and lambda carrageenan is essentially devoid of these units. Carrageenans are also characterized by the amount of ester sulfate groups that are present on both the galactose and anhydrogalactose units. The ester sulfate content of iota carrageenan may range from about 25% to 34%, preferably about 32%. This is intermediate between kappa carrageenan which has a 25% ester sulfate content and lambda carrageenan which has a 35% ester sulfate content. The sodium salt of iota carrageenan is soluble in cold water, but different grades of iota carrageenan require heating water to different temperatures to dissolve them. The iota carrageenans which are suitable for the microcrystalline cellulose/iota carrageenan material of this invention are soluble in water heated up to 80xc2x0 C. (176xc2x0 F.). Preferred grades of iota carrageenan are soluble at lower temperatures, for example, at 50xc2x0 C. (122xc2x0 F.), including but not limited to sodium iota carrageenan.
In the coating compositions of this invention, a film forming amount of carrageenan must be employed. A suitable film forming amount of carrageenan is generally in the range of about 9% to about 25% by dry weight of the coating composition, advantageously in the range of about 10% to about 20% of the dry weight of the composition.
The microcrystalline cellulose and carrageenan may be coprocessed or may be blended in any suitable manner, such as dry blending.
Coprocessed microcrystalline cellulose/iota carrageenan is rapidly peptizable. Peptization means that the dry agent can readily be dispersed in water in a colloidal state. Peptization of a dry agent in aqueous media allows the functionality of the agent to be restored to a level near or preferably at the level observed before the agent was dried. Rapidly peptizable dry agents can be dispersed (peptized) in a colloidal state with minimal agitation. Thus, the novel coating formulations in which the coprocessed microcrystalline cellulose/iota carrageenan is incorporated can be hydrated in as little as 0.5 hour, but more preferably require 1 to 3 hours. The common practice of preparing the coating formulation on the preceding day may be avoided, although it may also be continued, if this is preferable, without harming the formulation. If the formulation is prepared on one day and then used the next day, prior to being used, the formulation must be stirred for a short while to restore it to its flowable state.
The coprocessed microcrystalline/iota carrageenan compositions useful in this invention may be prepared by first attriting hydrolyzed cellulose wetcake, such that the average particle size of the wetcake particles is generally not more than about 20 microns, preferably less than about 10 microns, dispersing the attrited wetcake in water heated to a temperature above the temperature at which the particular grade of iota carrageenan being used dissolves, adding the dry carrageenan to the dispersion of microcrystalline cellulose, mixing the components, preferably homogenizing the mixture to assure intimate mixing, and drying the dispersion. Spray-drying is normally used to prepare the dried materials useful in this invention, but other methods of drying the dispersion may equally be acceptable.
It is possible to prepare the coatings directly, that is, before the drying of the wetcake, from a dispersion of microcrystalline cellulose wetcake and the carrageenan by accounting for the water present in the wetcake and adding the other ingredients in the formulation to this dispersion. Although this method of operation may be preferred for some coating operations, it is usually preferable to use the spray-dried, or otherwise dried, material because transportation costs for a dispersion would be less economical. Furthermore, drying by any method may enhance the association of the microcrystalline cellulose with the carrageenan, which may result in a more satisfactory prompt release coating.
Dry blended microcrystalline cellulose (e.g., Avicel(copyright) PH-105, average particle size 20 microns) and iota carrageenan, has been found to provide coating compositions that are at least equal to, and in some cases, superior to, coating compositions prepared from coprocessed microcrystalline cellulose/carrageenan.
Carrageenan by itself is known to be a natural film forming hydrocolloid when an aqueous dispersion thereof is spread on a surface and allowed to dry. However, the film is considered to be too weak for pharmaceutical tablets as shown by the results in Comparative Example A and therefore requires the presence of microcrystalline cellulose for satisfactory results.
A dry, physical blend of iota carrageenan and microcrystalline cellulose (Avicel(copyright) PH-102, average particle size 100 microns) also yielded what appear to be commercially unsatisfactory results in Comparative Example B. Thus, for commercial purposes, it is believed that the average particle size of the microcrystalline cellulose used in a dry blend with the natural, film forming hydrocolloid should be below 100 microns, advantageously below about 50 microns, preferably in the range of about 1-50 microns, more preferably, about 1-30 microns. Elegant, high performance coating formulations within the scope of this invention may be prepared from such dry, physical blends of microcrystalline cellulose and carrageenan.
A wide range of weight ratios of microcrystalline cellulose to carrageenan of from 90:10 to about 15:85 may be employed in this invention. In those applications which require a higher ratio microcrystalline cellulose to carrageenan in the MCC:CGN weight ratio generally ranges from about 90:10 to about 60:40, particularly from about 85:15 to about 65:35, more particularly, approximately 70:30. In certain embodiments of this invention it has been found that relatively lesser amounts of microcrystalline cellulose can be employed, such that the ratio of MCC:CGN can be in the range of from about 15:85 up to 60:40, preferably up to 55:45, and most preferably up to 50:50. A particular advantage for the dry, physical blends is that the ratio can be easily changed by simple blending techniques rather than manufacturing different ratios of coprocessed material. Thus, the dry, physical blends provide significantly greater flexibility for specific applications having different requirements. Pharmaceutical and veterinary solid dosage forms containing certain active ingredients may require increased carrageenan content in the composition to ideally coat the tablets. For these pharmaceutical and veterinary applications, a preferred weight ratio of microcrystalline cellulose to carrageenan is in the range of about 75:25 to about 25:75.
Regardless of whether the composition is based on coprocessed microcrystalline cellulose/carrageenan or a dry, physical blend of microcrystalline cellulose and carrageenan, a strengthening polymer, preferably, hydroxyethylcellulose (HEC) or polyvinylpyrrolidone (PVP), a plasticizer or both a strengthening polymer and a plasticizer and/or a surface active agent may be present in the coating formulation of this invention.
Other strengthening polymers which can provide the same benefit and may be used instead of HEC include HPMC, hydroxypropylcellulose, ethylcellulose, and methylcellulose; however, care must be exercised in the use of such alternative materials to avoid significantly retarding release of active ingredients and/or bioavailability. The preferred amount of strengthening polymer is less than the total amount of microcrystalline cellulose and carrageenan present in the composition. Depending on the desired hardness of the coating, the strengthening polymer may be employed in the composition at a level of about 0.5% to about 30%, to provide strength and improved appearance to the coating. This strength can be demonstrated by casting films of coating formulations on a flat, non-adherent surface, cutting strips of uniform width from the casting, and subjecting the strips to tensile testing on, e.g., an Instron Tensile Tester. The results of these tests show a very significant increase in tensile strength and decreased brittleness of the film when HEC or another strengthening polymer is included in the formulation. Strengthening polymers suitable for use in this invention and which will not significantly retard release from tablets or other solid dosage forms, are those polymers having a viscosity equal to or less than 20 mPaxc2x7s in a 2% aqueous solution at 20xc2x0 C. When a strengthening polymer is employed in the formulation in absence of a plasticizer, it is generally employed at about 5% to about 30% by dry weight coating composition.
In a preferred composition a conventional plasticizer is also included in the coating composition. Suitable plasticizers include polyethylene glycol, advantageously a high molecular weight polyethylene glycol, triacetin, dibutyl sebacate, propylene glycol, sorbitol, glycerin, and triethyl citrate. Of these, polyethylene glycol is preferred. These plasticizers may be employed in the coating compositions of the invention at a level of 18% to about 36% by dry weight of the coating composition, most preferably at a level of 31% to 35% by dry weight of the coating composition.
The prompt release coating compositions of the invention may include at least one filler. Such fillers may include, for example, calcium carbonate, dicalcium phosphate and carbohydrates, such as starch, maltodextrin, lactose, mannitol and other sugars. Of these, maltodextrin, mannitol and lactose are preferred fillers.
The prompt release coating compositions of the invention may include at least one surfactant. Such surfactants include either anionic or nonionic surfactants. Useful surfactants may be, e.g., sodium lauryl sulfate, hydroxylated soy lecithin (lecithin), polysorbates, and block copolymers of propylene oxide and ethylene oxide. Lecithin has been found to be particularly desirable in certain coating compositions of this invention and is suitably utilized at a level of about 2% to about 10% by dry weight of the formulation.
Coloring agents and opacifiers may also be used in these coatings or added to a suspension thereof including aluminum lakes, insoluble pigments, water-soluble dyes, titanium dioxide, and talc. Stearic acid or a salt or ester thereof, may be included at a level of about 1% to about 5% by dry weight of the composition to increase gloss of the coating, particularly when a plasticizer is not employed in the composition. Likewise propylene glycol alginate, may be used in small quantities (about 5% to about 10% by dry weight of the composition) to increase the gloss of the coating, as shown in Example 31.
A coating formulation of this invention may be sold as a dry powder formulation or as a ready-to-use dispersion in water. For aqueous dispersions it is preferred that these be prepared under aseptic conditions. Heating the water to an elevated temperature, for example, 85xc2x0 C., prior to preparation of the dispersion has shown that bacteria, mold, and yeast growth are prevented for at least 48 hours on agar pour plates. Therefore, if the containers for the dispersion are properly sanitized and then kept closed after being filled until they are used, there is little likelihood of bacteria, mold, or yeast growing in the dispersion. Alternatively, if a formulation is to be sold as an aqueous dispersion to be stored for a period of time, a preservative may be added. A combination of methyl paraben and propyl paraben has been found to be useful in this regard.
On a dry weight percentage basis a preferred composition of this invention comprises at least about 43%, suitably about 45% to about 75% of microcrystalline cellulose and carrageenan powder combined, more preferably about 45% to about 60%; about 0.5% to about 30% of strengthening polymer, more preferably about 7% to about 22%; and about 25% to about 40% of plasticizer, more preferably about 31% to about 35%; and an inert filler at about 2% to about 28%. Optionally, about 1% to about 30% of the formulation may comprise edible coloring agents and opacificiers such as talc or titanium dioxide, including from 1% to about 8% of coloring component such as a food dye or pigment, preferably about 1% to about 3%. Other optional ingredients may include a surfactant at about 0.5% to about 10%, advantageously 0.5 to about 7%, preferably 1.25% to 3% when a filler such as maltodextrin or mannitol is present. When no filler is employed higher amounts of surfactants such as lecithin may be employed at a level of about 5% to about 20%. Preservatives, such as methyl paraben at 0.75% to 1.50% and/or propyl paraben at 0.075% to 0.15% may also be present in the formulation. When maltodextrin is the filler, it is generally employed at about 2% to about 7% by dry weight of the composition, whereas when mannitol is the filler it is generally employed at about 10% to about 25% by dry weight of the formulation. These fillers may be employed alone or in combination within the ranges specified above.
The low level of fillers present in these coating formulations, particularly when the opacifier is titanium dioxide, enables the formulator to utilize relatively small amounts of coloring agent. Since coloring agents are quite costly, this provides a significant cost reduction from those formulations requiring from 6% to about 16% to effectively color prior art coating formulations.
Several other embodiments of this invention may be specifically mentioned as being of special interest to this invention, in which there is provided an edible, hardenable, prompt release coating composition comprising about 3% to 40% microcrystalline cellulose in combination with about 9% to about 25% iota carrageenan and at least one of a strengthening polymer, a plasticizer, or a surface active agent, wherein said coating composition is rapidly hydratable and does not, when ingested or placed in an aqueous medium, significantly retard release of active ingredients from a substrate to which said coating is applied. Any of the strengthening polymers, plasticizers, surface active agents, coloring agents, etc, set forth herein, may be used in this embodiment.
For example, a first of these embodiments comprises an edible, hardenable, prompt release coating composition comprising about 5% to about 25%, more particularly about 5% to 10%, microcrystalline cellulose; about 10% to about 16%, more specifically about 14% to 16%, iota carrageenan. Such embodiments may also contain about 2% to about 10% of a surface active agent such as lecithin, about 35% to about 70% of a filler such as lactose as a filler and/or about 5% to about 10% propylene glycol alginate. These compositions my also contain 5% to 22% of a strengthening polymer such as polyvinylpyrrolidone or hydroxyethylcellulose. A mixture of strengthening polymers such as PVP and HEC may also be employed. In addition, from about 2% to 10% of a coloring agent may be included to provide pigmented coating composition. These compositions may also contain at least one filler such as maltodextrin, dicalcium phosphate, croscarmellose sodium and a mixture thereof. In this embodiment a reduced level of microcrystalline cellulose may be employed together with a small amount of surface active agent, with a high level of lactose used as the filler. Such a particular composition may comprise 5% to 10% microcrystalline cellulose, 14%to 16% iota carrageenan, 2% to 4% hydroxylated soy lecithin, 65% to 70% lactose, and may include from about 5% to about 10% propylene glycol alginate. The MCC:CGN weight ratio in this embodiment may be in the range of about 15:85 up to 60:40, or more particularly 15:85 to about 50:50; and the combined total of microcrystalline cellulose and carrageenan comprises from about 20% to about 40% of the coating composition. When PVP is used as the sole strengthening polymer, it is preferably employed at a level of about 5% to about 16%, whereas, when HEC is used as the sole strengthening polymer, it is preferably employed at a level of about 20% to about 22%. Specific examples of this embodiment are set forth as Examples 36-53 in Table 1 below.
A second of these embodiments of the coating composition of this invention comprises about 30% to about 40%, in particular about 33% to about 38%, microcrystalline cellulose; about 10% to about 20%, more specifically about 14% to about 17%, iota carrageenan, and about 12% to about 25%, more specifically about 12% to about 22% of a strengthening polymer such as hydroxyethylcellulose. These compositions may also further comprise about 5% to about 10%, more particularly 7% to 10%, of a surface active agent such as hydroxylated soy lecithin, about 8% to about 15% of a filler such as lactose, maltodextrin and a combination thereof, more particularly about 5% to about 10% lactose, and optionally from 5% to about 10% of a coloring agent. In this embodiment, if maltodextrin is the filler, it may be present at a level of about 3% to about 5%, specifically about 3%, in combination with a filler such as lactose at a level of about 7% to about 10%, more specifically about 8% to 9%. A suitable variation comprises compositions which, in addition to MCC, CGN and HEC, further comprise from about 30% to about 36, more particularly about 34% to about 35% polyethylene glycol and about 4% to about 5% coloring agent. In this group of compositions the weight ratio MCC:CGN may be in the range of about 60:40 to about 75:35, and the combined weight of MCC and CGN may be about 48% to about 60% by weight of the composition. It is also noted that this embodiment may contain a suitable coloring agent. This embodiment is illustrated in Examples 54-57 of Table 1 below.
Finally, a third embodiment of the composition of this invention comprises 30% to 40%, more specifically about 33% to about 38% microcrystalline cellulose, 10% to 20%, more specifically about 13% to about 16%, iota carrageenan, about 10% to about 15% of a strengthening polymer such as polyvinylpyrrolidone, and 30% to 40%, more specifically 33% to 36%, of a plasticizer such as polyethylene glycol. This embodiment may further comprise from about 2% to about 10% of a coloring agent. In this embodiment the weight ratio of MCC:CGN may be in the range of about 60:40 to about 75:25 and the combined weight of MCC and CGN comprises about 50% to about 60% by weight of the composition. A suitable coloring agent may be included in the compsotions of this embodiment. Example 58 of Table 1 illustrates this embodiment.
The viscosity of the hydrated formulation can be important. It ideally should be low enough to be pumped to a spray unit continuously and then sprayed evenly in a useful pattern onto the substrate being coated. A useful concentration of the dry ingredients in water on a weight percentage basis, therefore, may be about 6% to about 15%, advantageously 6.5% to 11%, preferably about 8% to about 11%. To assure uniformity of the coating composition, it may be preferable to maintain agitation of the aqueous dispersion during the entire period of its being sprayed onto the pharmaceutical or veterinary solid dosage forms, confectionery, seeds, animal feed, fertilizer, pesticide tablets, or food.
The preferred edible, hardenable, prompt release coating formulations of this invention may generally be prepared and used according to a simple procedure. A dry mixture of coprocessed microcrystalline cellulose/carrageenan powder or a dry blend of microcrystalline cellulose and carrageenan, and a strengthening polymer, such as hydroxyethylcellulose, polyethylene glycol or other acceptable plasticizer, optionally together with a solid filler such as maltodextrin, lactose, mannitol or the like, preservatives, and/or surfactants are blended to form dry coating composition. Addition of edible coloring agents, for example, a water-soluble dye or a pigment, may precede the hydration step required to prepare the final coating formulation. This dry mixture is then added slowly to the vortex of stirred, purified water. Stirring of this mixture is continued for a sufficient period to allow all of the components to be fully hydrated. If a colored coating material is required a water soluble dye or a pigment may also be added, preferably as a dispersion or solution, to the hydrated coating composition. Optionally surfactants, and/or plasticizers may also be added at this stage of the process.
In the formulations of microcrystalline cellulose and iota carrageenan, a simple propeller mixer provides adequate agitation for rapid hydration. The period of hydration may be as short as 0.5 hour. It may, and preferably should, be longer, but more than 3 hours is not believed to be necessary. Hydration can take place at room temperature or at elevated temperatures as high as 65.5xc2x0 C. (150xc2x0 F.), preferably at a temperature about 48.9xc2x0 C. (120xc2x0 F.). The time required for full hydration and the viscosity of the dispersion are both considerably reduced when the dispersion is prepared at an elevated temperature, but coating dispersions prepared at ambient temperature only require an increase in hydration time and a slight reduction in solids content to perform completely satisfactorily. As previously stated, these formulations may be prepared on the day preceding the coating operation, if that is more convenient; however, a period of mixing will be required to overcome the thixotropic behavior of a formulation which sets up during overnight storage. Unlike coating formulations based primarily on hydroxyalkyl ethers of cellulose, for example, HPMC, constant stirring of the microcrystalline and carrageenan-based formulations of this invention does not need to be continued throughout the coating procedure, but mixing may continue, if preferred.
Any commercial spray coater may be used to apply the coating. Examples of useful coaters are Vector High Coaters manufactured by Vector Corporation and Accela-Cota manufactured by Thomas Engineering. Equipment variables which one skilled in the art can manipulate to provide an elegant coating based on the microcrystalline cellulose and carrageenan materials, either coprocessed or dry blended, include inlet temperature, outlet temperature, air flow, speed of rotation of the coating pan, and the rate at which the coating formulation is pumped to the coater. It is important that the inlet and outlet temperatures be controlled so that they are high enough to efficiently dry the coating to prevent the tumbling action of the already-coated tablets from damaging the newly-applied coating before more coating is applied to the same tablets.
Hydroxyethylcellulose binds water more effectively than carrageenan does. Thus, the presence of the major amount of carrageenan in the formulations of this invention has a significant effect on the speed of drying of the edible coatings. Drying times are reduced considerably because of the presence of the carrageenan which dilutes the negative effect of HEC on drying time. Thus, in the case of low melting active pharmaceutical agents, for example, ibuprofen, the outlet temperature can be reduced and still provide short enough drying time to be commercially useful.
Hydroxyethylcellulose is particularly susceptible to clogging spray nozzles at high temperatures. An additional benefit provided by the formulations of this invention is the avoidance of clogging of the spray nozzles with dispersions being sprayed at high temperatures.
The level of coating applied to pharmaceutical or veterinary dosage forms is preferably between about 0.5% to about 4% by weight of the uncoated dosage form, more preferably about 2% to about 3.5%, by weight of the uncoated dosage form. This level of coating will provide an elegant, serviceable coating to a wide variety of dosage forms. To apply a heavier coating to tablets would not be economical, and it might adversely affect disintegration of the tablets or other properties. Too light a coating would not provide optimal properties normally expected from a coating, for example, improved friability or adequate taste masking.
For confections the coating level should be about 5% to about 10% by weight of the uncoated confection. Seed coatings should be in the range of about 3% to about 6% by weight of the uncoated seeds. Fertilizers and pesticide tablets and granules benefit from coating of 1% to about 3%, by weight of the uncoated granules or tablets.
From the following examples it has been shown that the coatings of the present invention may be applied successfully to tablets having a wide variety of active ingredients incorporated therein. For example, it has been reported that multivitamin tablets are difficult to coat because of the lipophilic surface properties of the vitamins. Similarly, ibuprofen is a challenging active ingredient to coat. Tablets comprising both of these difficult-to-coat active ingredients have been coated readily with the instant invention, providing elegant tablets. Additionally, the coatings have been applied to tablets which have been debossed with letters or a logo without bridging which would hide, or even obliterate, the debossed design.
An additional utility of the coating formulations of this invention is as a replacement for sugar coating of tablets. A sugar coating is applied primarily to increase the weight and/or size of the tablet, but this is an old art which presents numerous problems. It is, therefore, desirable to replace the traditional sugar coating with a more easily applied coating as shown in Example 26. This coating procedure has the additional advantage that no top coat is required to be applied as it is done with a sugar coating
Storage of coated tablets under ambient temperature and humidity and 40xc2x0 C. and 75% relative humidity for one to three months has demonstrated that no significant degradation has occurred. These tablets have disintegrated within the same length of time as the same batch of newly coated tablets did, and in each case provided dissolution rates and times substantially equal to those of the uncoated tablets used as a substrate for coating. This is an additional unexpected benefit of the coatings based on carrageenan and microcrystalline cellulose, and it differs from the known drawbacks of HPMC.
All components of the formulation are typically pharmaceutically acceptable, edible food grade materials.
The following examples, in which percentages are weight percent and tablet hardness is in Kiloponds (Kp), are provided to demonstrate the method of preparation and application of these elegant coatings, but they are not intended to be limiting as to amounts and the type of optional ingredients or the specific method of application of the tablet coating described herein.